Tryptamine analogues as 5-ht1-like agonists

ABSTRACT

A compound of structure (I), in which A 1  is O, S(O) n  in which n is 0, 1 or 2, NR, CH 2 , or CH(OH); A 2  is a bond or CH 2  ; or A 1  A 2  is CH═CH; R is hydrogen or C 1-4  alkyl; R 1  is an optionally substituted 6- to 10-membered aryl or heteroaryl ring; suitably R 1  is an optionally substituted 6- 10-membered aryl ring such as phenyl or naphthyl; suitably R 1  is optionally substituted 6- to 10-membered heteroaryl ring, containing from 1 to 4 nitrogen atoms; R 2  is hydrogen, halogen, C 1-4  alkyl, CN, NO 2  or CF 3  ; R 3  is C(R 4 )(R 5 )CH 2  NR 6  R 7 , --CH═NNHC(NH)NH 2  or a; R 4  and R 5  are independently hydrogen or C 1-4  alkyl; R 6  and R 7  are the same or different and are each hydrogen or C 1-4  alkyl or together with the nitrogen atom to which they are attached form a ring; R 8  is hydrogen, C 1-4  alkyl, or C 3-6  alkenyl; the dotted lines represent an optional bond; and q and m are independently 1 or 2; and pharmaceutically acceptable salts, solvates and hydrates thereof. The compounds are 5-HT 1  -like agonists (or partial agonists) and as such are expected to have utility in medicine in the treatment and/or prophylaxis of migraine, and other conditions associated with cephalic pain, such as cluster headache, headache associated with vascular disorders and other neuralgia. They are also expected to have utility in the treatment of prophylaxis of portal hypertension. ##STR1##

This application is a National Stage Application of PCT/EP93/03563 filedDec. 14, 1993 which published as WO 94/14770 on Jul. 7, 1994.

This application is a National Stage Application of PCT/EP93/03563 filedDec. 14, 1993 which published as WO 94/14770 on Jul. 7, 1994.

The present invention relates to novel tryptamine analogues, processesand intermediates useful in their preparation, pharmaceuticalcompositions containing them and their use in therapy, in particular forthe treatment and/or prophylaxis of disorders characterised by excessivevasodilatation, such as migraine and portal hypertension.

WO-A-93/11106 published after the priority date of the presentapplication describes indole derivatives as serotonin (5HT₁) agonists.The generic disclosure of this document overlaps with the presentapplication in describing compounds of structure (I) as hereinafterdescribed wherein:

R¹ is a 6- to 10-membered aryl or heteroaryl ring optionally substitutedby up to 3 groups selected from halo, C₁₋₄ alkyl, CO₂ R⁹, NHCOR⁹, CONR¹⁰R¹¹, SO₂ NR¹⁰ R¹¹, NHSO₂ R¹², NO₂, NR¹⁰ R¹¹, NHCONH₂ or CN,

A¹ A² is O, S or NH,

R² is hydrogen and

R³ is (CH₂)₂ NR⁶ R⁷ or ##STR2##

WO-A-93/11106 also specifically discloses as Example 1G a compoundwherein R¹ is 3-CF₃ -2-pyridyl, A¹ A² is NH, R² is hydrogen and R³ isCH₂ CH₂ NMe₂.

The present invention provides, in a first aspect, a compound ofstructure (I): ##STR3## in which A¹ is O, S(O)_(n) in which n is 0,1 or2, NR, CH₂, or CH(OH);

A² is a bond or CH₂ ; or

A¹ A² is CH═CH,

R is hydrogen or C₁₋₄ alkyl,

R¹ is an optionally substituted 6- to 10-membered aryl or heteroarylring;

R² is hydrogen, halogen, C₁₋₄ alkyl, CN, NO₂ or CF₃ ;

R³ is C(R⁴)(R⁵)CH₂ NR⁶ R⁷, --CH═NNHC(NH)NH₂ or ##STR4## R⁴ and R⁵ areindependently hydrogen or C₁₋₄ alkyl; R⁶ and R⁷ are the same ordifferent and are each hydrogen or C₁₋₄ alkyl or together with thenitrogen atom to which they are attached form a ring;

R⁸ is hydrogen, C₁₋₄ alkyl, or C₃₋₆ alkenyl;

the dotted lines represent an optional bond; and

q and m are independently 1 or 2;

and pharmaceutically acceptable salts, solvates and hydrates thereof.

Suitably A¹ is O, S, NR or CH₂.

Suitably A² is a bond or CH₂.

Suitably R¹ is an optionally substituted 6- or 10-membered aryl ringsuch as phenyl or naphthyl.

Suitably R¹ is an optionally substituted 6- to 10-membered heteroarylring containing from 1 to 4 nitrogen atoms. Examples of such heteroarylrings include pyridine, pyridazine, pyrimidine, pyrazine, triazine,quinoline, or quinazoline. Particular examples are pyridine, pyridazine,pyrimidine, pyrazine and quinoline.

The heteroaryl ring can be linked to A¹ A² via a carbon or nitrogen atomof the heteroaryl ring.

Suitably R¹ is unsubstituted or substituted by up to 3 groups selectedfrom halo, C₁₋₄ alkyl, hydroxy, oxo, C₁₋₄ alkoxy, --CO₂ R⁹, --NHCOR⁹,--CONR¹⁰ R¹¹, --SO₂ NR¹⁰ R¹¹, --NHSO₂ R¹², NO₂, --NR¹⁰ R¹¹, --NHCONH₂,CN, CF₃ or CF₃ O wherein R⁹ to R¹¹ are independently hydrogen or C₁₋₄alkyl and R¹² is C₁₋₄ alkyl.

Suitably, R² is hydrogen, halogen, C₁₋₄ alkyl, CN, NO₂ or CF₃.Preferably R² is hydrogen or halogen, in particular hydrogen orchlorine.

Suitably R³ is C(R⁴)(R⁵)CH₂ NR⁶ R⁷, or --CH═NNHC(NH)NH₂.

Suitably, R⁴ and R⁵ are hydrogen or C₁₋₄ alkyl. Preferably R⁴ and R⁵ areboth hydrogen or methyl.

Suitably, R⁶ and R⁷ are the same or different and are each hydrogen orC₁₋₄ alkyl or together with the nitrogen atom to which they are attachedform a ring. Preferably R⁶ and R⁷ are both hydrogen or methyl.

Suitable rings formed by R⁶ and R⁷ together with the nitrogen atom towhich they are attached include for, example, 5- or 6-membered ringssuch as pyrrolidino and piperidino rings.

Suitably R³ is a group ##STR5##

Examples of C₁₋₄ alkyl groups (alone or as part of another group, e.g.C₁₋₄ alkoxy) include methyl, ethyl, propyl or butyl which can bestraight chain or branched.

Examples of halo groups include fluoro, bromo, chloro or iodo.

Particular compounds of structure (I) include:

3-(2-N,N-dimethylaminoethyl)-5-phenoxyindole,

3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole,

1-amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane,

1-amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane,

1-amino-2-(5 -(3-trifluoromethylphenoxy)indol-3 -yl)ethane,

1-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane,

3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole,

3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole,

3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole,

1-amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane,1-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,

3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole,

1-(N,N-dimethylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane,

1-(N,N-dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane,

3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole,

1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, and

4-chloro-3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole, and,

pharmaceutically acceptable salts, solvates or hydrates thereof.

Pharmaceutically acceptable acid addition salts of the compounds ofstructure (I) include, for example, those formed with inorganic acidse.g. hydrochloric, sulphuric, methanesulphonic or phosphoric acids andorganic acids e.g. succinic, maleic, citric, (D) and (L) tartaric,acetic or fumaric acid. Other non-pharmaceutically acceptable salts e.g.oxalates may be used for example in the isolation of compounds offormula (I), and are included within the scope of this invention. Alsoincluded within the scope of the invention are solvates and hydrates ofcompounds of formula (I).

It will be appreciated that certain compounds of structure (I) forexample where R⁴ is other than hydrogen may contain an asymmetriccentre. Such compounds will exist as two (or more) optical isomers(enantiomers). Both the pure enantiomers, racemic mixtures (50% of eachenantiomer) and unequal mixtures of the two, are included within thescope of the present invention. Further, all diastereomeric formspossible (pure enantiomers and mixtures thereof) are within the scope ofthe invention.

The compounds of the present invention can be prepared by processesanalogous to those known in the art. The present invention thereforeprovides, in a further aspect, a process for the preparation of acompound of structure (I) or a salt, solvate or hydrate thereof, whichcomprises:

(a) for compounds in which R³ is C(R⁴)(R⁵)CH₂ NR⁶ R⁷ reduction of acompound of structure (II): ##STR6## (in which A¹, A², R¹ and R² are asdescribed for structure (I) and Y is a reducible group) optionally inthe presence of a compound of the formula R⁶ R⁷ NH in which R⁶ and R⁷are as described for structure (I); or

(b) reaction of a compound of structure (III): ##STR7## (wherein A¹, A²,R¹ and R² are as hereinbefore defined) or a salt thereof, with acompound of structure (IV):

    R.sup.3 CH.sub.2 CHO                                       Structure (IV)

or a protected derivative (e.g. an acetal or ketal) thereof wherein R³is as described for structure (I); or

(c) for compounds where R³ is ##STR8## reaction of a compound ofstructure (V): ##STR9## (wherein A¹, A², R¹ and R² are as hereinbeforedefined) with a compound of structure (VI): ##STR10## (wherein R¹³ is aN-protecting group or R⁸ as hereinbefore defined and q and m are ashereinbefore defined), and if required removing the N-protecting group;or

(d) for compounds where R³ is --CH═NNHC(NH)NH₂, reaction of a compoundof structure (VII): ##STR11## where A¹, A², R¹ and R² are ashereinbefore defined with aminoguanidine or an acid addition saltthereof;

and thereafter optionally

converting a group R¹ into another group R¹ ;

converting a group R² into another group R² ;

forming a pharmaceutically acceptable salt or hydrate thereof.

In compounds of structure (II) Y may be a group which is converted to--C(R⁴)(R⁵)CH₂ NR⁶ R⁷ when reduced in the presence of R⁶ R⁷ NH, in whichcase examples of Y include --C(R⁴)(R⁵)CN; and --C(R⁴)(R⁵)CHO.Alternatively Y may be a group which itself can be reduced to--C(R⁴)(R⁵)CH₂ NR⁶ R⁷, such groups including --C(R⁴)(R⁵)CH₂ NO₂,--C(R⁴)(R⁵)CH₂ N₃, --COCONR⁶ R⁷, --C(R⁴)(R⁵)CONR⁶ R⁷, --C(R⁴)═CHNO₂ and--C(R⁴)(R⁵)CH₂ NR⁶ COR⁷.

It will be appreciated that the precise method of reduction will dependon the nature of the group Y, such methods being well known in the art.

When Y represents --C(R⁴)(R⁵)CHO or --C(R⁴)(R⁵)CN the reaction between acompound of structure (II) and an amine R⁶ R⁷ NH is suitably carried outunder reductive amination conditions, for example, catalytichydrogenation in the presence of the amine R⁶ R⁷ NH and a suitablesolvent. Suitable catalysts include, for example, Raney nickel. Suitablesolvents include, for example, C₁₋₄ alkanols, in particular methanol.The reaction is carried out at ambient temperature or elevatedtemperature for as long as is necessary for the reaction to be complete.Preferred reaction conditions include, for example for compounds inwhich R⁶ and R⁷ are both hydrogen, hydrogenation in methanolic ammoniain the presence of a Raney nickel catalyst; and where R⁶ and R⁷ are bothC₁₋₄ alkyl, for example methyl, hydrogenation in the presence ofdimethylamine in methanol as solvent and Raney nickel as catalyst.

When Y represents a group --C(R⁴)(R⁵)CH₂ NO₂, --C(R⁴)(R⁵)CH₂ N₃,--COCONR⁶ R⁷, or --C(R⁴)(R⁵)CONR⁶ R⁷ the reduction may be effected forexample using allane (prepared from lithium aluminium hydride andsulphuric acid) or lithium aluminium hydride in a solvent such astetrahydrofuran. Alternatively a group --C(R⁴)(R⁵)CH₂ NO₂ may be reducedby catalytic hydrogenation, using for example palladium on charcoal orby treatment with cobalt boride prepared by treating a cobalt II saltsuch as cobalt chloride with sodium borohydride in a suitable solventsuch as methanol.

Reduction of a group --C(R⁴)(R⁵)CH₂ NR⁶ COR⁷ may be accomplished using ahydride such as lithium aluminium hydride.

It will be appreciated that a variety of other substituents Y andmethods of reduction are well-known in tryptamine chemistry, such asthose described in GB 2185020A, and may also be employed in process (a).

The intermediate compounds of structure (II) can be prepared by standardprocedures.

Thus, compounds of structure (II) wherein Y represents --CH₂ CN may beprepared from the corresponding gramine (i.e. 3-dimethylaminomethyl)compound by cyanation e.g. using potassium cyanide. The graminederivative may be obtained by reaction of the 3-unsubstituted indolewith bisdimethylaminomethane in the presence of acetyl chloride and in asuitable solvent, such as dichloromethane. A 3-unsubstituted indole maybe prepared from an appropriately substituted nitrotoluene derivativeaccording to the following reaction scheme 1: ##STR12##

Alternatively a 3-unsubstituted indole may be obtained from anappropriately substituted benzaldehyde derivative according to thefollowing reaction scheme 2: ##STR13##

When Y represents --C(R⁴)(R⁵)CH₂ NR⁶ COR⁷ a compound of structure (II)may be prepared by reacting a corresponding aminoethyl compound with anacylating agent, for example an anhydride such as acetic or propionicanhydride or a mixture of an acid with an anhydride e.g. formic acid andacetic anhydride. This intermediate provides a convenient method ofpreparing compounds of structure (I) wherein one of R⁶ and R⁷ ishydrogen and the other a C₁₋₄ alkyl group.

A compound of structure (II) wherein Y represents --COCONR⁶ R⁷ may beprepared from an indole of structure (VIII): ##STR14## by reaction withoxalyl chloride followed by an amine HNR⁶ R⁷ and subsequentlyintroducing the group R². When R² is halogen e.g. iodine this may beintroduced by reaction of a compound of structure II where R² is H and Yis COCONR⁶ R⁷ with an appropriate halide e.g. potassium iodide in anacidic medium such as trifluoroacetic acid in the presence of thalliumtrifluoroacetate.

A compound of structure (II) wherein Y represents --C(R⁴)(R⁵)CHO may beprepared for example by oxidation of the corresponding alcohol, using anoxidising agent such as pyridinium chlorochromate, or dimethylsulphoxidewith oxalylchloride and triethylamine.

The alcohol may itself be obtained by a cyclisation analogous to process(b). The alcohol may aim be converted to a halide derivative and thenceto an azide using standard procedures, to give a compound of structure(II) wherein Y represents --C(R⁴)(R⁵)CH₂ N₃.

A compound of structure (V) wherein A¹ A² is S, CH₂, CH(OH), CH═CH,CH(OH)CH₂ or CH₂ CH₂ can be prepared by reacting a compound of structure(IX): ##STR15## wherein R¹⁴ is a N-protecting group and R¹⁵ is a groupR² as hereinbefore defined or a precursor thereof with an appropriateelectrophile and thereafter removing the N-protecting group andthereafter if necessary converting a group R¹⁵ to a group R².

Appropriate electrophiles include R¹ SSR¹, R¹ (CH₂)_(p) L¹ (wherein p is1 or 2 and L¹ is a suitable leaving group such as halo, e.g. bromo oriodo), R¹ CHO or ##STR16##

The reaction with the epoxide results in compounds wherein A¹ A² isCH(OH)CH₂ which can be dehydrated in the presence of acid to CH═CH. Thereaction with the aldehyde results in compounds wherein A¹ A² is CH(OH)which can be reduced for example by catalytic hydrogenation to CH₂.

Suitable N-protecting groups include trialkylsilyl groups in particulartriisopropylsilyl which can be removed in standard manner, e.g. bytreatment with tetra-n-butylammonium fluoride in a suitable solvent suchas tetrahydrofuran or dichloromethane.

An example of a precursor of the group R² is hydrogen which is asuitable precursor for halogen as hereinbefore described for theintroduction of such a group into a compound of structure (VIII).

A compound of structure (IX) can be suitably prepared by reacting acompound of structure (X): ##STR17## wherein L² is a suitable leavinggroup such as halo, e.g. bromo or iodo and R¹⁴ and R¹⁵ are ashereinbefore defined with a lithiating reagent such as tert-butyllithium or n-butyl lithium in a solvent such as diethyl ether ortetrahydrofuran at low temperature preferably -60° C.

The N-protecting group can be induced in standard manner, e.g. bytreating with triisopropylsilyl chloride in dimethylformamide in thepresence of sodium hydride as base.

A compound of structure (V) wherein A¹ A² is S can be prepared byreacting a compound of structure (XI): ##STR18## wherein L³ is asuitable leaving group such as halo, e.g. bromo or iodo, ortrifluoromethane sulphonyloxy, R¹⁵ is as hereinbefore defined and R¹⁶ ishydrogen or a group R¹⁴ as hereinbefore defined with a compound of theformula R¹ SSn(R¹⁷)₃ where R¹⁷ is C₁₋₄ alkyl in the presence of apalladium catalyst such as palladium tetrakistriphenyl phosphinepalladium (O) in an organic solvent such as toluene according to themethod of M. Kosugi et al. Bull Chem Soc Jpn 1985, 58, 3657, andthereafter if required removing the group R¹⁴ and/or converting a groupR¹⁵ to a group R².

A compound of structure (V) wherein A¹ A² is CH₂, CH═CH or CH₂ CH₂ canbe prepared by reacting a compound of structure (XI) as hereinbeforedefined with a compound of formula R¹ A¹ A² ZnX wherein X is halo suchas chloro or bromo in the presence of a palladium catalyst such aspalladium tetrakistriphenyl phosphine palladium (O) in an organicsolvent such as tetrahydrofuran at ambient or preferably refluxtemperature, and thereafter if required removing the group R¹⁴ and/orconverting a group R¹⁵ to a group R².

A compound of structure (V) wherein A¹ A² is CH═CH or CH₂ CH₂ can beprepared by reacting a compound of structure (XI) as hereinbeforedefined with a compound of formula R¹ CH═CH₂ and thereafter if requiredreducing the product with for example palladium on charcoal under anatmosphere of hydrogen and/or removing the group R¹⁴ and/or converting agroup R¹⁵ to a group R².

A compound of structure (V) wherein A¹ A² is OCH₂, SCH₂ or NRCH₂ can beprepared by reacting a compound of structure (XII): ##STR19## wherein L⁴is a suitable leaving group such as halo e.g. bromo or iodo, ortrifluoromethane sulphonyloxy and R¹⁵ and R¹⁶ are as hereinbeforedefined with a compound of formula R¹ OH, R¹ SH or R¹ NHR in thepresence of a suitable base such as potassium carbonate or potassiumhydrogen carbonate in an organic solvent such as dimethylsulphoxide ordimethyl formamide at ambient or preferably reflux temperature, andthereafter if required removing the group R¹⁴ and/or converting a groupR¹⁵ to a group R².

A compound of structure (V) wherein A¹ A² is CH₂, SCH₂, CH(OH)CH₂, CH═CHor CH₂ CH₂ can be prepared by reacting a compound of structure (XIII):##STR20## wherein L⁵ is halo such as bromo or iodo and R¹⁴ and R¹⁵ areas hereinbefore defined with an appropriate electrophile and thereafterremoving the N-protecting group and if required converting a group R¹⁵to a group R². Appropriate electrophiles include R¹ L¹, R¹ SSR¹, R¹ CHOor R¹ CH₂ L¹ wherein L¹ is as herebefore defined.

A compound of structure (XIII) can be prepared in standard manner byreacting a compound of structure (XII) wherein L⁴ is halo and R¹⁶ is agroup R¹⁴ with magnesium.

A compound of structure (V) wherein A¹ A² is O, S or NR can be preparedby reacting optionally in the presence of a suitable base such aspotassium hydroxide a compound of structure (XIV): ##STR21## wherein Xis O, S or NR and R¹⁵ and R¹⁶ are as hereinbefore defined with acompound of formula R¹ L¹ wherein R¹ is as hereinbefore defined and itsnature allows nucleophillic aromatic substitution and L¹ is a suitableleaving group such as halo, and thereafter if required removing thegroup R¹⁴ and/or converting a group R¹⁵ to the group R².

The chemistry hereinbefore described for preparing a compound ofstructure (V) can be similarly used for preparing a compound ofstructure (XV): ##STR22## which is the starting material of Scheme 1,except that instead of the compounds of structure (XI) or (XII) are usedcompounds of structure (XVI): ##STR23## wherein D is L³ or L⁴ CH₂ andL³, L⁴ and R¹⁵ are as hereinbefore defined.

A compound of structure (XV) wherein A¹ A² is O, S or NR can be preparedby reacting a compound of structure (XVI) wherein D is fluoro with R¹OH, R¹ SH or R¹ NHR in a dipolar aprotic solvent such as dimethylsulphoxide or dimethylformamide in the presence of a base such aspotassium carbonate at ambient or preferably elevated temperatures inparticular the boiling point of the solvent, and thereafter if requiredconverting a group R¹⁵ to a group R².

Cyclisation according to process (b) is a standard method for preparingindole compounds and may be effected by methods well known in the art,for example by heating a compound of structure (III) with a compound ofstructure (IV) in a non-aqueous solvent such as acetic acid or anaqueous or non-aqueous solvent e.g. an alcohol such as methanol in thepresence of an acid catalyst such as hydrochloric acid or a Lewis acidsuch as boron trifluoride, or in the presence of an acidic ion exchangeresin.

A compound of structure (III) may be obtained from the correspondinganiline derivative by diazotisation, for example using sodium nitriteand concentrated hydrochloric acid, and subsequent reduction.

In process (c) the reaction of a compound of structure (V) with acompound of structure (VI) is suitably performed in the presence of abase e.g. sodium methoxide in an organic solvent such as a C₁₋₂ alkanolat ambient temperature or elevated temperature e.g. 30°-50° C.,conveniently at the reflux temperature of the reaction mixture.Alternatively the reaction can be carried out under acidic conditions,e.g. in acetic acid at elevated temperature (e.g. 30°-100° C.). When R¹³is a N-protecting group for example tert-butoxycarbonyl this can beremoved in standard manner for example by treatment with HCl in methanolor with trifluoroacetic acid.

In process (d) a compound of the structure (VII) is suitably reactedwith an acid addition salt of aminoguanidine, e.g. the hydrochloride, ina suitable solvent such as a C₁₋₄ alkanol, e.g. methanol or ethanol atambient or preferably elevated temperature, e.g. 30°-100° C.,conveniently at the reflux temperature of the reaction mixture.

A compound of the structure (VII) can suitably be prepared by reacting acompound of structure (V) as hereinbefore defined with a Vilsmeierreagent formed from phosphoryl chloride and dimethylformamide followedby aqueous work-up in the presence of a base such as sodium hydroxide.

Suitable interconversions of R¹ groups, and of R² groups, will beapparent to those skilled in the art and can be carried out by standardprocedures.

Acid addition salts of compounds (I) can be prepared by standardprocedures, for example, by reaction with suitable organic and inorganicacids, the nature of which will be apparent to persons skilled in theart.

Compounds of structure (I) have affinity for the 5-HT₁ -like receptorand are expected to be useful in treating disease states which requiremodulation of the 5-HT₁ -like receptor. In particular the compounds are5-HT₁ -like agonists (or partial agonists) and as such are expected tohave utility in medicine in the treatment and/or prophylaxis ofmigraine, and other conditions associated with cephalic pain, such ascluster headache, headache associated with vascular disorders and otherneuralgia. They are also expected to have utility in the treatment orprophylaxis of portal hypertension.

In a further aspect, the invention provides a method of treatment ofconditions which require alteration of the 5-HT₁ -like receptor inparticular migraine or portal hypertension which comprises administeringto a subject in need thereof an effective amount of a compound ofstructure (I) or a pharmaceutically acceptable salt, solvate or hydratethereof.

For use in medicine, the compounds of the present invention are usuallyadministered in a standard pharmaceutical composition. The presentinvention therefore provides in a further aspect pharmaceuticalcompositions comprising a compound of structure (I) or apharmaceutically acceptable salt, solvate or hydrate thereof and apharmaceutically acceptable carrier.

The compounds of the invention may be administered by any convenientroute, for example by oral, parenteral, buccal, sublingual, nasal,rectal or transdermal administration and the pharmaceutical compositionsadapted accordingly.

The compounds of structure (I) and their pharmaceutically acceptablesalts which are active when given orally can be formulated as liquids,for example syrups, suspensions or emulsions, tablets, capsules andlozenges.

A liquid formulation will generally consist of a suspension or solutionof the compound or pharmaceutically acceptable salt in a suitable liquidcarrier(s) for example, ethanol, glycerine, non-aqueous solvent, forexample polyethylene glycol, oils, or water with a suspending agent,preservative, flavouring or colouring agent.

A composition in the form of a tablet can be prepared using any suitablepharmaceutical carrier(s) routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose.

A composition in the form of a capsule can be prepared using routineencapsulation procedures. For example, pellets containing the activeingredient can be prepared using standard carriers and then filled intoa hard gelatin capsule; alternatively, a dispersion or suspension can beprepared using any suitable pharmaceutical carrier(s), for exampleaqueous gums, celluloses, silicates or oils and the dispersion orsuspension then filled into a soft gelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilised and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal once the contents of the container have been exhausted. Wherethe dosage form comprises an aerosol dispenser, it will contain apropellant which can be a compressed gas such as compressed air or anorganic propellant such as a fluorochlorohydrocarbon. The aerosol dosageforms can also take the form of a pump-atomiser.

Compositions suitable for buccal or sublingual administration includetablets, lozenges and pastilles, wherein the active ingredient isformulated with a carrier such as sugar and acacia, tragacanth, orgelatin and glycerin.

Compositions for rectal administration are conveniently in the form ofsuppositories containing a conventional suppository base such as cocoabutter.

Compositions suitable for transdermal administration include ointments,gels and patches.

Preferably the composition is in unit dose form such as a tablet,capsule or ampoule.

Each dosage unit for oral administration contains preferably from 1 to250 mg (and for parenteral administration contains preferably from 0.1to 25 mg) of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof calculated as the free base.

The pharmaceutically acceptable compounds of the invention will normallybe administered in a daily dosage regimen (for an adult patient) of, forexample, an oral dose of between 1 mg and500 mg, preferably between 10mg and 400 mg e.g. between 10 mg and 250 mg, or an intravenous,subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg,preferably between 0.1 mg and 50 mg e.g. between 1 mg and 25 mg, of thecompound of the formula (I) or a pharmaceutically acceptable saltthereof calculated as the free base, the compound being administered 1to 4 times per day. Suitably the compounds will be administered for aperiod of continuous therapy, for example for a week or more.

BIOLOGICAL DATA 5-HT₁ -like Receptor Screen RABBIT BASILAR ARTERY

Experiments were performed in intracranial arteries from rabbit isolatedbasilar artery in a similar method to one described previously (Parsonsand Whalley, 1989. Eur J Pharmacol 174, 189-196.).

In brief, rabbits were killed by overdose with anaesthetic (sodiumpentobarbitone). The whole brain was quickly removed and immersed in icecold modified Kreb's solution and the basilar artery removed with theaid of a dissecting microscope. The Krebs solution was of the followingcomposition (mM) Na⁺ (120); K⁺ (5); Ca²⁺ (2.25); Mg²⁺ (0.5); Cl⁻ (98.5);SO₄ ²⁻ (1); EDTA (0.04), equilibrated with 95% O₂ /5% CO₂. Theendothelium was removed by a gentle rubbing of the lumen with a finemetal wire. Arteries were then cut into ring segments (ca 4-5 mm wide)and set up for recording of isometric tension in 50 ml tissue baths inmodified Krebs solution with the additional supplement of (mM); Na²⁺(20); fumarate (10); pyruvate (5); L-glutamate (5) and glucose (10). Thearteries were then placed under a resting force of 3-4 mN maintained at37° C. and the solution bubbled with 95% O₂ /5% CO₂.

After tests for initial reactivity with 90 mM KCl depolarising solutionand for lack of acetylcholine-induced relaxation of 5-HT (10 mM)precontraction, cumulative concentration-effect curves (2 nM-60 mM) to5-HT were constructed in the presence of ascorbate 200 mM, cocaine 6 mM,indomethacin 2.8 mM, ketanserin 1 mM and prazosin 1 mM.

Following a 45-60 min wash period, cumulative concentration-effectcurves to the test compounds or 5-HT (as a time match control) wereconstructed in the presence of ascorbate, indomethacin, cocaine,ketanserin and prazosin.

The compounds of Examples 1, 2, 3A, 3B, 4A, 8, 10B, 12 and 16 had EC₅₀values (concentration for half-maximal contraction) in the range 0.025to 4.2 μM.

EXAMPLE 1 3-(2-N,N-Dimethylaminoethyl)-5-phenoxyindole

(a) A mixture of 5-fluoro-2-nitrotoluene (9.8 g), phenol (11.89 g),potassium carbonate (12.22 g) and copper bronze (1.0 g) was boiled for16 hours. After cooling to room temperature the mixture was extractedwith boiling diethyl ether (2×500 ml) and the combined organic phaseswashed with aqueous 1N sodium hydroxide (6×100 ml) and water (3×100 ml).After drying (MgSO₄), solvent was removed at reduced pressure and theresidue column chromatographed (silica gel, hexane→5% diethylether/hexane eluant) to give 2-nitro-5-phenoxytoluene (2.06 g) as anoil.

¹ H NMR (CDCl₃) 2.59(s,3H), 6.81-6.85(m,2H), 7.06(d,2H), 7.23-7.27(m,1H)7.38-7.46(m,2H) and 8.04(m,1H).

(b) A solution of 2-nitro-5-phenoxytoluene (2.06 g) in dimethylformamide(30 ml) containing dimethylformamide diethylacetal (1.57 g) andpyrrolidine (0.77 g) was heated at 120° C. for 2 hours. Solvent wasremoved at reduced pressure and the residue dissolved in methanol. RaneyNickel (one spatula measure) was added followed by hydrazine hydrate(3×0.5 ml portions, one portion every 30 minutes). The mixture wasstirred for a further 1 hour after the final portion of hydrazinehydrate was added, the mixture filtered and solvent removed at reducedpressure. The residue was partitioned between water (100 ml) and diethylether (100 ml), the organic phase separated and dried (MgSO₄), solventremoved at reduced pressure and the residue column chromatographed(silica gel, hexane →10% ethyl acetate/hexane eluant) to give5-phenoxyindole (0.52 g).

¹ H NMR (d₆ -DMSO) 6.40(m,1H), 6.80-6.91(m,3H), 7.02(t,1H), 7.20(m, 1H),7.26-7.44(m,4H) and 11.16(br.s,1H).

(c) To a cooled (ice bath) solution of bis (dimethylamino)methane (0.34g) in dichloromethane (25 ml), acetyl chloride was added dropwise over 5minutes. After stirring for 10 minutes, 5-phenoxyindole (0.51 g) wasadded and stirring continued for a further one hour at room temperature.The mixture was basified with aqueous 2N sodium hydroxide, brine (50 ml)added and the organic phase separated washed with water (2×50 ml), dried(MgSO₄) and the solvent removed at reduced pressure. The residue wasdissolved in dimethylformamide (25 ml) and potassium cyanide (0.62 g)and iodomethane (0.61 g) added. After stirring for 48 hours, the mixturewas diluted with water (50 ml) and extracted with ethyl acetate (3×50ml). The combined organic phases were washed with water (4×50 ml), dried(MgSO₄) and solvent removed at reduced pressure to give3-cyanomethyl-5-phenoxyindole (0.57 g).

¹ H NMR (d₆ -DMSO) 4.01(s,2H), 6.87-6.92(m,3H), 7.03(t,1H),7.28-7.45(m,5H)

(d) To a solution of 3-cyanomethyl-5-phenoxyindole (0.57 g) in methanol(25ml) containing dimethylamine (10 ml) Raney nickel (one spatula) wasadded and the mixture shaken under 45 psi hydrogen pressure for 2 hours.The catalyst was removed by filtration, solvent removed at reducedpressure and the residue column chromatographed (silica gel,dichloromethane/10% methanol in ammonia 0→8% eluant) to give the titlecompound (0.035 g) from which the oxalate salt was prepared by theaddition of oxalic acid (0.024 g) in methanol (1 ml) followed by diethylether to the cloud point to give the oxalate salt m.p. 170°-173° C.

EXAMPLE 2 3-(2-N,N-Dimethylaminoethyl)-5-phenylthioindole

(a) Triisopropylsilyl chloride (6.87 g) was added to the sodium saltprepared from 5bromoindole (6.35 g) and sodium hydride (1.71 g, 50%suspension in oil) in dimethylformamide (32 ml) and the mixture wasstirred at room temperature for 2 hours then poured into ice water (150ml). The crude intermediate obtained by evaporation of thedichloromethane extract was column chromatographed (silica gel, 40°-60°C. petroleum ether) to give 5-bromo-1-triisopropylsilylindole isolatedas an oil.

(b) 5-Bromo-1-triisopropylsilylindole (6.74 g) was dissolved intetrahydrofuran (100 ml) cooled (CO₂ /acetone) and tert butyl lithium(40 ml, 1.7M in pentane) added over 30 minutes. Stirring of the deepyellow solution was continued for a further 1 hour, diphenyl disulphide(21 g) in tetrahydrofuran (30 ml) added, the mixture warmed to roomtemperature overnight, tetrabutylammonium fluoride (50 ml, 1M intetrahydrofuran) added and stirring continued for a further 2 hours.Water (200 ml) was added and the mixture extracted with diethyl ether(3×100 ml). The combined organic phase was washed with brine (100 ml)dried (MgSO₄) and the solvent removed at reduced pressure. The residuewas column chromatographed (silica gel, hexane/diethyl ether 0-40%eluant) appropriate fractions combined, solvent removed and the residuerecrystallised from hexane/diethyl ether to give 5-phenylthioindole(2.21 g) m.p.97°-99° C.

(c) Oxalyl chloride (0.57 g) in diethyl ether ((2 ml) was added dropwiseover 5 minutes to 5-phenylthioindole (0.75 g) in diethyl ether (10 ml)with ice cooling. After stirring for 1 hour the precipitated solid wascollected by filtration dissolved in dichloromethane (40 ml) and asaturated solution of dimethylamine in diethyl ether (4 ml) added. Afterstirring for 1 hour the mixture was diluted with dichloromethane (40 ml)and washed with 10% aqueous potassium carbonate (2×ml) water (2×30 ml)and brine (30 ml). The organic phase was dried (MgSO₄) and the solventremoved at reduced pressure. The residue was triturated with ethylacetate/diethyl ether to give3-N,N-dimethylglyoxamido-5-phenylthioindole (0.78 g), m.p. 163°-166° C.

(d) To a solution of 3-N,N-dimethylglyoxamido-5-phenylthioindole (0.4 g)in tetrahydrofuran (70 ml) alane [prepared from lithium aluminiumhydride (0.76 g) and conc. sulphuric acid (1.0 g) in tetrahydrofuran (50ml)] was added and the mixture stirred for 16 hours. After quenching bythe dropwise addition of water the mixture was filtered (celite pad) andsolvent removed at reduced pressure. The residue was partitioned betweendichloromethane (50 ml) and 1M hydrochloric acid (50 ml). The organicphase was separated, dried (MgSO₄) and the solvent removed at reducedpressure. The residue was triturated with diethyl ether/ethyl acetate togive the title compound (0.20 g) m.p. softens >162° C.

¹ H NMRδ(d₆ -DMSO) 2.81(s,6H), 3.12(m,2H), 3.30(m,2H), 7.06(d,2H),7.12(t,1H), 7.23(m,3H), 7.35(s,1H), 7.46(s,1H), 7.91(s,1H), 10.36(br.s,1H) and 11.32(s,1 H).

EXAMPLE 3 1-Amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane (3A) and1-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane (3B)

a) Sodium metal (2.01 g, 87.43 mmol) cut into small pieces was dissolvedin absolute ethanol (67 mL) and the resulting solution cooled to -5° C.A mixture of ethyl azidoacetate (11.32 g, 87.67 mmol) and3-(4-methoxyphenoxy) benzaldehyde (5.0 g, 21.91 mmol) was added dropwiseover 30 min. On completion of addition the mixture was stirred at -5° C.for 4.5 hr, and then kept at room temperature overnight. The redreaction mixture was poured into saturated aqueous NH₄ Cl solution andextracted (3×) with Et₂ O. The ethereal extracts were washed (H₂ O andthen saturated aqueous NaCl), dried (MgSO₄) and evaporated to give anorange gum which was chromatographed (silica gel; hexane/Et₂ O; 0-15%).The product: ethyl 2-azido-3-(3-(4-methoxyphenoxy)phenyl)propenoate, wasthus obtained as a light yellow gum, 5.5 g (70%).

b) The vinyl azide (4.40 g, 12.97 mmol) was dissolved in dry,redistilled xylene (250 mL) and added dropwise to refluxing xylene (280mL) under an atmosphere of nitrogen. Once addition was complete, refluxwas maintained for 4.5 hr. After cooling, the xylene was evaporated invacuo and the resulting yellow solid was chromatographed (silica gel;hexane/Et₂ O; 0-21%). Two products were obtained: (i) ethyl7-(4-methoxyphenoxy)indole-2-carboxylate, (R_(f) =0.35; hexane/Et₂ O)colourless plates ex hexane, 0.957 g (24%), and (ii) ethyl5-(4-methoxyphenoxy)indole-2-carboxylate, (R_(f) =0.19; hexane/Et₂ O)colourless needles ex hexane/toluene (3:1 ), 1.661 g (41%).

c) Ethyl 5-(4-methoxyphenoxy)indole-2-carboxylate (1.60 g, 5.14 mmol)was heated in methanolic NaOH (3.2M, 9.1 mL), at reflux for 1 hr. Theresulting thick paste was added to water and brought to pH 2 with 5MHCl. The flocculent precipitate of acid thus formed was extracted intoEtOAc (3×) and the combined organic layers washed with saturated aqueousNaCl, dried (MgSO₄) and evaporated to give, as an off-white solid:5-(4-methoxyphenoxy)indole-2-carboxylic acid, 1.40 g (96%).

d) The carboxylic acid (1.3 g, 4.59 mmol) was suspended in dry Et₂ O,and the mixture cooled in a dry-ice/acetone bath. Pre-condensed liquidammonia (ca 20 mL) was added, and the mixture was stirred. The coolingwas removed and the mixture allowed to warm to room temperature, whilethe excess ammonia evaporated. The remaining ether was evaporated invacuo leaving the ammonium salt as a coating around the inside of theflask. This was then fitted with an air condenser and, under anatmosphere of N₂, the flask was heated over a microburner. The solidmelted and darkened, and vigourous gas evolution was observed. Aftercooling the material was dissolved in CH₂ Cl₂ and washed with aq. K₂ CO₃solution (2×) followed by brine, dried (MgSO₄) and evaporated to a darkoil which was distilled (kugelrohr; 250° C. at ca 0.5 mbar) giving:5-(4-methoxyphenoxy)indole as a colourless oil which solidified to acrystalline mass on standing, 0.95 g (87%).

e) N,N,N',N'-Tetramethyldiaminomethane (0.29 g, 0.39 mL, 2.82 mmol) wasdissolved in CH₂ Cl₂ (dry; 8.5 mL) and the stirred solution cooled in anice-bath. Acetyl chloride (0.23 g, 0.21 mL, 2.95 mmol) was addeddropwise (syringe) over 10 min, to give a white suspension. Afterstirring for a further 20 min. with cooling maintained, a solution of5-(4-methoxyphenoxy)indole (0.5 g, 2.09 mmol) in CH₂ Cl₂ (7.2 mL) wasadded dropwise, over 20 min. The cooling was removed and the resultingclear solution was stirred for 1 hr at room temperature. The solutionwas then diluted with CH₂ Cl₂, washed with 10% aq. NaOH (2×) followed bysaturated aqueous NACl and dried (MgSO₄). Evaporation in vacuo gave3-(N,N-dimethylaminomethyl)-5-(4-methoxyphenoxy)indole as a gum. Thismaterial was dissolved in DMF (dry; 7 mL) and potassium cyanide (0.52 g,8.0 mmol) was added, followed by methyl iodide (1.19 g, 0.52 mL, 8.35mmol). The mixture became cloudy and eventually opaque. After stirringat room temperature for 36 hr, water was added and the mixture wasextracted with Et₂ O (2×). The combined organic layers were washed withH₂ O (2×) and then with saturated aqueous NaCl, dried (MgSO₄) andevaporated to give an almost colourless gum. This was triturated withEt₂ O to give: 3-cyanomethyl-5-(4-methoxyphenoxy)indole as a virtuallycolourless solid, 0.334 g (57%).

f) The cyanomethyI compound (0.31 g, 1.114 mmol) was dissolved in MeOH(15 mL) and the solution cooled (dry-ice/acetone bath). Pre-condenseddimethylamine (ca 15 mL) was added, followed by Raney nickel (onespatula). The mixture was hydrogenated at ca 45 psi (room temperature)for 1.5 hr. The catalyst was filtered off, and the filtrate evaporatedto a gum, This was dissolved in ^(i) PrOH (10 mL) and treated withdi-tert-butyl dicarbonate (0.25 g, 1.15 mmol). After stirring at roomtemperature for 1 hr, the mixture was evaporated to a gum, which waschromatographed (silica gel; hexane/Et₂ O; 0-60% and then CH₂ Cl₂ /EtOHcontaining 2% concentrated aqueous NH₃ ; 0-18%). Two products wereobtained: (i)1-tert-butoxycarbonylamino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane; acolourless gum, (0.088 g, 21%) which eluted in 60% Et₂ O/hexane, and(ii) 1-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane; agum (0.166 g, 48%), which required the more polar eluant describedabove. The less polar product was dissolved in MeOH (0.5 mL) and treatedwith ethereal HCl (1.0M, 2 mL). After standing at ca 4° C. for 2 hr, thesolution was evaporated to dryness. The residue was redissolved in MeOH(0.5 mL) and on addition of Et₂ O small, slightly pink plates wereobtained of: 1-amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethanehydrochloride (3A), 0.054 g, (15%), m.p. 207°-26° C. (decomp.). The morepolar column fraction was dissolved in methanol and treated with oxalicacid (0.10 g, 1.11 mmol). Addition of Et₂ O to the pale yellow solutiongave, as small, slightly off-white crystals:1-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane oxalate(3B), 0.116 g (26%), m.p. 166°-70° C.

In a similar manner to that described above for Examples 3A and 3B, thefollowing pairs of compounds were synthesised.

EXAMPLE 4 1-Amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane (4A) and1-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane (4B)

a) As previously described, sodium ethoxide was prepared from sodiummetal (2.16 g, 93.95 mmol) in EtOH (72 mL) and after cooling, a mixtureof ethyl azidoacetate (12.17 g, 94.25 mmol) and3-(4-methylphenoxy)benzaldehyde (5.0 g, 23.56 mmol) was added. After 4.5hr the reaction was worked-up, and chromatography (silica gel;hexane/Et₂ O; 0-5%) gave the product: ethyl2-azido-3-(3-(4-methylphenoxy)phenyl)propenoate as a yellow oil, 4.50 g(59%).

b) The azide (3.38 g, 10.46 mmol) in xylene (170 mL) was added torefluxing xylene (180 mL) under an atmosphere of N₂. After refluxing for3.5 hr the solution was cooled and evaporated, and the residue waschromatographed (silica gel; hexane/Et₂ O) to give two products: (i)ethyl 7-(4-methylphenoxy)indole-2-carboxylate, colourless needles fromhexane, 0.797 g (20%), and (ii) ethyl5-(4-methylphenoxy)indole-2-carboxylate, colourless crystals fromhexane/toluene, 1.752 g (43%).

c) Ethyl 5-(4-methylphenoxy)indole-2-carboxylate (1.0 g, 3.39 mmol) washydrolysed in methanolic NaOH (3.2M, 6.0 mL) at reflux, for 1 hr. Afterwork-up the product: 5-(4-methylphenoxy)indole-2-carboxylic acid wasobtained as an almost white solid, 0.92 g (ca 100%).

d) The carboxylic acid (0.72 g, 2.69 mmol) was converted to its ammoniumsalt, which was heated (microburner) to give a dark oil. This wasdistilled (kugelrohr, 250° C. at ca 1 mbar) giving5-(4-methylphenoxy)indole, a colourless gum, which solidified on storagein the freezer, 0.417 g (70%).

e) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.24 g, 0.32 mL, 2.35 mmol) in CH₂ Cl₂ (7 mL) with acetyl chloride(0.19 g, 0.17 mL, 2.39 mmol) followed by a solution of5-(4-methylphenoxy)indole (0.39 g, 1.74 mmol) in CH₂ Cl₂ (6 mL), gaveafter work-up: 3-(N,N-dimethylaminomethyl)-5-(4-methylphenoxy)indole asa gum. This was treated with potassium cyanide (0.43 g, 6.6 mmol) andmethyl iodide (0.98 g, 0.43 mL, 6.9 mmol) in DMF (6 mL) for 16 hr, andafter appropriate work-up, 3-cyanomethyl-5-(4-methylphenoxy)indole wasobtained as an off-white crystalline solid 0.338 g (74%).

f) The cyanomethyl compound (0.324 g, 1.235 mmol) was hydrogenated inMeOH (9 mL) and Me₂ NH (7 mL) over Raney nickel, at room temperature and45 psi. After work-up and treatment with BOC₂ O (excess) in ^(i) PrOH,evaporation gave a gum which was chromatographed (silica gel; hexane/Et₂O; 0-50% and then CH₂ Cl₂ /EtOH containing 2% concentrated aqueous NH₃ ;0-14%). Two products were obtained: (i)1-tert-butoxycarbonylamino-2-(5-(4-methylphenoxy)indol-3-yl)ethane; agum (0.12 g) and (ii) 1-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane; a gum (0.19 g). Treatment of the less polar compoundwith HCl/Et₂ O in MeOH gave, as a faintly mauve crystalline solid:1-amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane hydrochloride (4A),0.063 g (17%), m.p. 230°-34° C. The more polar column fraction, ontreatment with oxalic acid (0.11 g) in MeOH (ca 1.5 mL) followed byaddition of Et₂ O, gave: 1-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane oxalate (4B ), off-white granularcrystals, 0.12 g (25%), m.p. 148°-52° C.

EXAMPLE 5 1-Amino-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane (5A)and1-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane(5B)

a) As previously described, sodium ethoxide was prepared from sodiummetal (1.58 g, 68.73 mmol) in EtOH (53 mL) and after cooling, a mixtureof ethyl azidoacetate (8.93 g, 69.16 mmol) and3-(3-trifluoromethylphenoxy)benzaldehyde (4.6 g, 17.28 mmol) was added.After 16 hr the reaction was worked-up, and chromatography (silica gel;hexane/Et₂ O; 0-3%) gave the product: ethyl2-azido-3-(3-(3-trifluoromethylphenoxy)phenyl)propenoate as a yellowoil, 3.52 g (54%).

b) The azide (3.50 g, 9.28 mmol) in xylene (150 mL) was added torefluxing xylene (172 mL) under an atmosphere of N₂. After refluxing for2 hr the solution was cooled and evaporated; and the residue waschromatographed (silica gel; hexane/Et₂ O) to give two products: (i)ethyl 7-(3-trifluoromethylphenoxy)indole-2-carboxylate, colourlessprisms from hexane, 0.886 g (27%), and (ii) ethyl5-(3-trifluoromethylphenoxy)indole-2-carboxylate, colourless needlesfrom hexane/toluene, 1.062 g (33%).

c) Ethyl 5-(3-trifluoromethylphenoxy)indole-2-carboxylate (0.8 g, 2.29mmol) was hydrolysed in methanolic NaOH (3.2M, 4.0 mL) at reflux, for 1hr. After work-up the product:5-(3-trifluoromethylphenoxy)indole-2-carboxylic acid was obtained as analmost white solid, 0.73 g (ca 100%).

d) The carboxylic acid (0.73 g, 2.27 mmol) was convened to its ammoniumsalt, which was heated (microburner) until tlc of the resulting dark oilshowed consumption of starting material. This oil was distilled(kugelrohr, 225° C. at ca 0.8 mbar) giving:5-(3-trifluoromethylphenoxy)indole, a virtually colourless oil, 0.537 g(85%).

e) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.26 g, 0.34 mL, 2.50 mmol) in CH₂ Cl₂ (7.3 mL) with acetyl chloride(0.20 g, 0.18 mL, 2.53 mmol) followed by a solution of5-(3-trifluoromethylphenoxy) indole (0.50 g, 1.79 mmol) in CH₂ Cl₂ (6.2mL), gave after work-up:3-(N,N-dimethylaminomethyl)-5-(3-trifluoromethylphenoxy)indole as a gum.This was treated with finely ground potassium cyanide (0.45 g, 6.9 mmol)and methyl iodide (1.03 g, 0.45 mL, 7.26 mmol) in DMF (9 mL) for 16 hr,and after appropriate work-up and chromatography (silica gel; hexane/Et₂O; 0-45%) 3-cyanomethyl-5-(3-trifluoromethylphenoxy)indole was obtainedas an almost colourless gum, 0.415 g (73%).

f) The cyanomethyl compound (0.4 g, 1.27 mmol) was hydrogenated in MeOH(18 mL) and Me₂ NH (14 mL) over Raney nickel, at room temperature and 40psi. After work-up and treatment with BOC₂ O (excess) in ^(i) PrOH,evaporation gave a gum which was chromatographed (silica gel; hexane/Et₂O; 0-60% and then CH₂ Cl₂ /EtOH containing 2% ) NH₃ ; 0-22%). Twoproducts were obtained: (i)1-tert-butoxycaxbonylamino-2-(5-(3-trifluoromethylphenoxy(indol-3-yl)ethane;a colourless gum (0.069 g) and (ii)1-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane;a gum (0.21 g). Treatment of the less polar compound with HCl/Et₂ O inMeOH gave, as white crystalline powder1-amino-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane hydrochloride(5A ), 0.023 g,(5%), m.p. 200°-08° C. The more polar column fraction, ontreatment with oxalic acid (0.083 g) in MeOH, followed by addition ofEt₂ O, gave small white crystals of:1-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethaneoxalate (5B), 0.151 g (27%), m.p. 169°-72° C.

EXAMPLE 6 1-(N,N-Dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane

a) 3-Phenoxybenzoic acid (20.0 g, 93.36 mmol) was added portionwise tothionyl chloride (20 mL) and the resulting mixture was refluxed for 1.5hr. After cooling, the excess SOCl₂ was evaporated in vacuo to give thecrude acid chloride as a brown oil. This was dissolved in CH₂ Cl₂ /THF(1:3; 95 mL) and the solution added dropwise to a stirred, ice cooledsolution of 2-amino-2-methyl propan-1-ol in CH₂ Cl₂ (185 mL), maintainedunder an atmosphere of N₂. The reaction mixture was stirred at roomtemperature for ca 16 hr, and was then washed with water (2×) andsaturated aqueous NaCl, dried (MgSO₄) and evaporated to a gum. Thismaterial was cooled (ice-bath) and thionyl chloride (18 mL) was addeddropwise, with stirring. The reaction mixture became warm and vigourousgas evolution was observed. After stirring at room temperature for 0.5hr, the excess SOCl₂ was evaporated in vacuo. The residue was suspendedin water and while cooling in an ice-bath, 20% NaOH aq. was added to capH 13. The mixture was extracted (2×) with CH₂ Cl₂ and the combinedextracts were washed with water (2×) and saturated aqueous NaCl, dried(MgSO₄) and evaporated to a gum. This was chromatographed (silica gel;hexane/Et₂ O) to give two products:

(i) 2-(3-phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole, (R_(f) =0.42,3:1 hexane/Et₂ O) a pale yellow oil, 12.72 g (51%) and

(ii) 2-(3-phenoxybenzamido)-2-methylpropyl benzoate. (R_(f) =0.26, 3:1hexane/Et₂ O) a pale yellow viscous gum, 8.98 g (20%).

b) 2-(3-Phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (4.5 g, 16.83mmol) was dissolved in THF (43 mL) and the solution was cooled to -65°C. ^(n) BuLi (2.5M in hexane; 9.5 mL) was added (syringe) at anappropriate rate to maintain the temperature below -60° C. The resultingorange-yellow solution was stirred at -65° C. for 45 min. and then asolution of N-chlorosuccinimide (2.25 g, 16.85 mmol) in THF (35 mL) wasadded, again ensuring that the temperature did not rise above -60° C.The mixture was allowed to warm gradually to room temperature andstirred overnight. After quenching with water and evaporation of thebulk of the THF in vacuo, the biphasic mixture was extracted with Et₂ O(2×). The combined ethereal extracts were washed with H₂ O and thensaturated aqueous NACl, dried (MgSO₄) and evaporated to a gum which waschromatographed (silica gel; hexane/Et₂ O; 0-17%) to afford twocompounds: firstly, unreacted starting material was recovered, 1.44 g(32%); and subsequently, the required product2-(2-chloro-3-phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole 2.81 g(55%), was obtained as a viscous gum.

c) 2-(2-Chloro-3-phenoxyphenyl)-4,4-dimethyl-4,5-dihydrooxazole (2.80 g,9.28 mmol) was heated with methyl iodide (1.8 mL) in nitromethane (4.0mL) for 24 hr, (bath temp ca 70° C.). The brown solution was allowed tocool and Et₂ O was added until a slight cloudiness was observed.Crystallization commenced almost immediately and the mixture was allowedto stand in the freezer overnight. Large off-white crystals of theproduct:2-(2-chloro-3-phenoxyphenyl)-3,4,4-trimethyl-4,5-dihydrooxazolium iodidewere obtained. 3.51 g, (85%).

d) The quaternary iodide (3.48 g, 7.83 mmol) was stirred in EtOH (34mL), and sodium borohydride (1.07 g, 28.28 mmol) was added portionwise,over ca 1 hr. After stirring for a further 1 hr, HCl (2M; 36 mL) wasadded with care. This mixture was stirred for 1 hr, and after saturatingwith NaCl, was extracted with Et₂ O (2×). The combined (brownish)extracts were washed with aq. Na₂ S₂ O₃, water and then saturatedaqueous NaCl; dried (MgSO₄) and evaporated to a gum. This was dissolvedin THF (30 mL) and 5M HCl was added to the point of cloudiness. Themixture was refluxed for 30 min. and after cooling, water was added,followed by solid potassium bicarbonate (carefully) until effervescenceceased. The THF was then removed in vacuo, NaCl added and the mixtureextracted with Et₂ O (2×). The combined extracts were washed with H₂ Oand then saturated aqueous NaCl, dried (MgSO₄) and evaporated to give,as a virtually colourless crystalline solid:2-chloro-3-phenoxybenzaldehyde, 1.35 g (74%).

From this point on the synthesis follows the route described above forExample 3.

e) Sodium ethoxide was prepared from sodium metal (0.50 g, 21.75 mmol)in EtOH (18 mL) and after cooling, a mixture of ethyl azidoacetate (2.88g, 22.31 mmol) and 2-chloro-3-phenoxybenzaldehyde (1.28 g, 5.47 mmol)was added. After 1.5 hr the reaction was worked-up, and chromatography(silica gel; hexane/Et₂ O; 0-10%) gave the product: ethyl2-azido-3-(2-chloro-3-phenoxy phenyl)propenoate as a yellow oil, 0.913 g(49%).

f) The azide (0.904 g, 2.63 mmol) in xylene (42 mL) was added torefluxing xylene (49 mL) under an atmosphere of N₂. After refluxing for1 hr the solution was cooled and evaporated, and the residue waschromatographed (silica gel; hexane/Et₂ O) to give the product: ethyl4-chloro-5-phenoxyindole-2-carboxylate; small very pale yellow crystalsfrom hexane/toluene, 0.313 g (37%).

g) Ethyl 4-chloro-5-phenoxyindole-2-carboxylate (0.302 g, 0.956 mmol)was hydrolysed in methanolic NaOH (3.2M, 1.7 mL) at reflux, for 1.5 hrAfter work-up, the product: 4-chloro-5-phenoxyindole-2-carboxylic acidwas obtained as an almost white solid, 0.275 g (ca 100%).

h) The carboxylic acid (0.22 g, 0.765 mmol) was heated (Varitemp heatgun,ca 400° C.) to give a dark oil. This was chromatographed (silicagel; hexane/Et₂ O) giving 4-chloro-5-phenoxyindole, as a greenish solid,0.147 g (79%).

i) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.083 g, 0.11 mL, 0.812 mmol) in CH₂ Cl₂ (2.4 mL) with acetyl chloride(0.064 g, 0.057 mL, 0.80 mmol) followed by a solution of4-chloro-5-phenoxy indole (0.14 g, 0.574 mmol) in CH₂ Cl₂ (2 mL), gaveafter work-up: 3-(N,N-dimethylaminomethyl)4-chloro-5-phenoxyindole, asan off-white solid. This was treated with potassium cyanide (0.143 g,2.19 mmol) and methyl iodide (0.0.33 g, 0.143 mL, 2.29 mmol) in DMF (1mL) for 16 hr After appropriate work-up and chromatography (silica gel;hexane/Et₂ O; 0-55%), 3-cyanomethyl-4-chloro-5-phenoxyindole wasobtained as an off-white crystalline solid, 0.094 g (58%).

j) The cyanomethyl compound (0.09 g, 0.318 mmol) was hydrogenated inMeOH (6 mL) and Me₂ NH (6 mL) over Raney nickel, at room temperature and40 psi. After work-up and treatment with BOC₂ O (0.06 g) in ^(i) PrOH(ca 2 mL), for 2 hr, evaporation gave a gum which was chromatographed(silica gel; hexane/Et₂ O; 0-60% and then CH₂ Cl₂ /EtOH containing 2%concentrated aqueous NH₃ ; 0-15%). The less polar component:1-(tert-butoxycarbonylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane wasobtained as a gum, 0.012 g (10%). The more polar component:1-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane, also agum, 0.035 g, (35%); was treated with oxalic: acid (0.02 g) in MeOH,followed by addition of Et₂ O, to give:1-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane oxalate, awhite crystalline solid, 0.034 g (26%), m.p. 163°-66° C.

EXAMPLE 73-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole

5-(4-Methoxyphenoxy)indole (as prepared above; 0.411 g, 1.72 mmol) and1-methyl-piperid-4-one (0.24 mL) were refluxed with sodium methoxide(0.108 g) in MeOH (24 mL) for 16 hr Tlc indicated that reaction was notcomplete and reflux was therefore continued over a 24 hr period. Overthis period further 4-methylpiperidone (4×0.24 mL) and NaOMe (0.108 g)were added. After standing at room temperature for 48 hr, the mixturewas diluted with water and the MeOH was evaporated in vacuo. Theresidual mixture was extracted with EtOAc (3×) and the combined extractswere washed with H₂ O and then saturated aqueous NaCl; dried (MgSO4) andevaporated to a yellow solid, which was chromatographed (silica gel; CH₂Cl₂ /EtOH), giving the product as a pale yellow solid. This wasdissolved in MeOH and treated with oxalic acid (0.15 g). On addition ofEt₂ O, yellow needles were obtained of:3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indoleoxalate, 0.283 g (39%), m.p. 157°-65° C. decomp.

EXAMPLE 8 3-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole

5-Phenoxyindole (0.30 g, 1.43 mmol), 1-methylpiperid-4-one (0.188 g, 0.2mL, 1.66 mmol) and sodium methoxide (0.09 g) were heated at reflux inMeOH (20 mL) for 20 hr. After cooling, water was added and most of theMeOH was evaporated in vacuo. The residual mixture was diluted withwater, extracted with EtOAc (2×) and the combined extracts were washedwith water, dried (MgSO₄) and evaporated to give:3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindole, a yellowsolid 0.243 g, (56%). The free base (0.1 g) was dissolved in MeOH andtreated with fumaric acid (0.057 g, 0.49 mmol). Et₂ O was added to thepoint of cloudiness and the mixture was kept at ca 4° C. for 48 hr, toafford: 3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenoxyindolefumarate, a pale yellow crystalline solid, 0.072 g (52%), m.p. 135°-37°C.

EXAMPLE 9 3-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole

This preparation was carried out in a similar manner to that of Example8.

5-Phenylthioindole (0.50 g, 2.22 mmol), 1-methylpiperid-4-one (0.292 g,0.32 mL, 2.58 mmol) and sodium methoxide (0.139 g) were heated at refluxin MeOH (25 mL) for 20 hr. After cooling and work-up,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole wasobtained as a pale yellow solid, 0.399 g, (56%). This free base (0.20 g)was treated with fumaric acid (0.11 g, 0.94 mmol) in MeOH/Et₂ O to give:3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole fumarate,0.124 g (46%), m.p. 225°-28° C.

EXAMPLE 10 1-Amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane (10A) and1-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane (10B)

a) To a solution of 3-hydroxypyridine (15.0 g, 157 mmol) in DMF (60 mL)were added potassium carbonate (15.36 g, 110 mmol) and copper powder(1.2 g). The mixture was stirred under N₂ for 15 min. and then asolution of 5-fluoro-2-nitrotoluene (12.29 g, 79 mmol) in DMF (10 mL)was added dropwise over ca 0.5 hr. The mixture was stirred at reflux for5 hr and then allowed to cool EtOAc was added and the black solidprecipitate produced, was removed by filtration and discarded. NaOH aq.(1M, 100 mL) was added, and the two-phase mixture filtered through Hyfloto remove insoluble tarry material. The EtOAc layer was then separated,dried (MgSO₄) and evaporated to give a dark oil. Chromatography (silicagel;hexane/EtOAc; 0-24%) gave the product:2-nitro-5-(pyrid-3-yloxy)toluene, a yellow solid, 8.0 g (22%).

b) 2-Nitro-5-(pyrid-3-yloxy)toluene (6 g, 26 mmol),dimethylformamidedimethyl acetal (5.43 g, 45 mmol) and pyrrolidine (3.24g, 45 mmol) were heated in DMF (70 mL) at reflux, for 3 hr. The DMF wasevaporated in vacuo to leave a deep red oil, which was dissolved in MeOH(200 mL) and the solution cooled in an ice-bath. Raney nickel (3spatulas) was added, followed by addition of hydrazine hydrate (24 mL;portionwise, to moderate the vigour of the reaction). Once addition wascomplete, the mixture was stirred for 1 hr at room temp and the Raneynickel residue was then removed by filtration. The filtrate wasevaporated and water added to the residue, which was then extracted withEtOAc (2×). The extracts were dried (MgSO₄) and evaporated to a gum,which was chromatographed (silica gel; hexane/EtOAc; 0-42%), giving, asa white solid: 5-(pyrid-3-yloxy)indole, 1.60 g (24%).

From this point the preparation follows closely the corresponding stagesof the synthesis of Example 3.

c) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.829 g, 1.11 mL, 8.12 mmol) in CH₂ Cl₂ (10 mL) with acetyl chloride(0.637 g, 0.573 mL, 8.12 mmol) followed by a solution of5-(pyrid-3-yloxy)indole (1.23 g, 5.8 mmol) in CH₂ Cl₂ (100 mL), gaveafter work-up: 3-(N,N-dimethylaminomethyl)-5-(pyrid-3-yloxy)indole as agum. This was treated with finely ground potassium cyanide (1.246 g, 19mmol) and methyl iodide (2.7 g, 1.18 mL, 19 mmol) in DMF (70 mL) for 16hr, and after appropriate work-up and chromatography (silica gel;hexane/EtOAc; 0-60%), 3-cyanomethyl-5-(pyrid-3-yloxy)indole was obtaineda gum, which solidified on standing, 0.655 g (45%).

d) The cyanomethyl compound (0.655 g, 2.6 mmol) was hydrogenated in MeOH(100 mL) and Me₂ NH (20 mL) over Raney nickel, at room temperature and50 psi. After work-up and treatment with BOC₂ O (excess) in ^(i) PrOH,evaporation gave a gum which was chromatographed (silica gel; hexane/Et₂O; 0-100% and then CH₂ Cl₂ /EtOH containing 2% concentrated aqueous NH₃; 0-15%). Two products were obtained: (i)1-tert-butoxycarbonylamino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane, acolourless gum, 0.10 g (11%) and (ii)1-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy) indol-3-yl)ethane; a gum,0.20 g (27%). Treatment of the less polar compound with HCl/Et₂ O inMeOH gave, as light brown hygroscopic solid:1-amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane hydrochloride (10A). Themore polar column fraction on treatment with oxalic acid in MeOH,followed by addition of Et₂ O, gave:1-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane oxalate(10B), m.p 178°-80° C.

EXAMPLE 11 1-Amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11A) and1-(N,N-dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane (11B)

a) A mixture of 5-hydroxyindole (2.50 g, 18.7 mmol), 2-chloropyrimidine(4.3 g, 37.6 mmol) and powdered KOH (1.049 g, 18.7 mmol) was warmed inDMSO (50 mL) at 40° C. for 5 hr, under an atmosphere of N₂. The darksolution was cooled and poured into saturated aqueous NaCl and themixture was extracted with EtOAc (3×). The extracts were dried andevaporated, and the residue was chromatographed (silica gel;hexane/EtOAc; 0-70%),giving, as a white solid:5-(pyrimidin-2-yloxy)indole, 1.12 g (28%).

From this point the preparation follows closely the corresponding stagesof the synthesis of Example 3.

b) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.854 g, 1.14 mL, 8.36 mmol) in CH₂ Cl₂ (10 mL) with acetyl chloride(0.657 g, 0.59 mL, 8.36 mmol) followed by a solution of5-(pyrimidin-2-yloxy)indole (1.268 g, 6.00 mmol) in CH₂ Cl₂ (110 mL),gave after work-up:3-(N,N-dimethylaminomethyl)-5-(pyrimidin-2-yloxy)indole as a yellowsolid. This was treated with finely ground potassium cyanide (1.37 g, 21mmol) and methyl iodide (2.94 g, 1.28 mL, 21 mmol) in DMF (70 mL) for 16hr, and after appropriate work-up,3-cyanomethyl-5-(pyrimidin-2-yloxy)indole was obtained as a light yellowsolid, 0.98 g (65%).

c) The cyanomethyl compound (0.98 g, 3.9 mmol) was hydrogenated in MeOH(150 mL) and Me₂ NH (20 mL) for 1 hr, over Raney nickel, at roomtemperature and 50 psi. After removal of the catalyst by filtration,evaporation gave a gum which was chromatographed (silica gel; CH₂ Cl₂/MeOH containing 10% concentrated aqueous NH₃ ; 0-10%). Two productswere obtained: (i)1-(N,N-dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane, a gum,0.32 g (29%) and (ii) 1-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,also a gum, 0.072 g (7%). Both free bases were converted into theirrespective oxalate salts by treatment with oxalic acid in MeOH/Et₂ O.The former amine gave:1-N,N-dimethylamino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane oxalate(11A), a white crystalline solid, m.p. 174°-76° C. The more polar aminegave: 1-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane oxalate (11B),an off-white solid m.p. 178°-80°.

EXAMPLE 123-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole

a) 2-Hydroxypyridine (5 g, 52 mmol), 5-fluoro-2-nitrotoluene (4.09 g,26.4 mmol), potassium carbonate (7.26 g, 52 mmol) and copper powder (0.5g) were heated together in DMF (10 mL), at reflux for 5 hr. Aftercooling, EtOAc was added and the resulting black solid precipitate wasremoved by filtration and discarded. The filtrate was washed with aq.NaOH (1M; 3×), dried (MgSO₄) and evaporated to give a dark yellow solid.This was chromatographed (silica gel; hexane/EtOAc; 0-100% and thenEtOAc/MeOH; 0-5%) giving: 2-nitro-5-(pyrid-2-yloxy)toluene, a lightyellow solid, 1.50 g (12% ).

b) 2-Nitro-5-(pyrid-2-yloxy)toluene (1.11 g, 4.82 mmol),dimethylformamide dimethylacetal (1.018 g, 8.54 mmol) and pyrrolidine(0.6 g, 84.36 mmol) were heated in DMF (25 mL) at reflux, for 3 hr. TheDMF was evaporated in vacuo to leave a deep red oil, which was dissolvedin MeOH (80 mL) and the solution cooled in an ice-bath. Raney nickel (2spatulas) was added, followed by addition of hydrazine hydrate (4 mL;portionwise, to moderate the vigour of the reaction). Once addition wascomplete, the mixture was stirred for 1.5 hr at room temp and the Raneynickel residue was then removed by filtration (Hyflo). The filtrate wasevaporated and water added to the residue giving a brown solid, whichwas collected by filtration and chromatographed (silica gel;hexane/EtOAc; 0-100% and then EtOAc/MeOH 0-3%) to afford, as a lightyellow solid: 5-(pyrid-2-yloxy)indole, 0.22 g (23%).

The remaining stage of this preparation was carried out in a similarmanner to that of Example 8.

c) 5-(Pyrid-2-yloxy)indole (0.22 g, 1.04 mmol), 1-methylpiperid-4-one(0.235 g, 2.08 mmol) and sodium methoxide (0.337 g) were heated atreflux in MeOH (20 mL) for 48 hr, over activated molecular sieves. Aftercooling and work-up, the residue was chromatographed (silica gel; CH₂Cl₂ /MeOH; 0-25%) to give3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole, agum, 0.083 g (26%). This free base was treated with oxalic acid inMeOH/Et₂ O to give:3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indoleoxalate, m.p. 240°-45° C.

EXAMPLE 13 1-(N,N-Dimethylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane

This preparation was carried out by adaptation of those of Examples 3and 8.

a) Phenol (73.02 g, 780 mmol), 5-fluoro-2-nitrotoluene (60.18 g, 390mmol), potassium carbonate (75.02 g, 540 mmol) and copper powder (3.0 g)were heated together in DMF (150 mL), at reflux for 16 hr. After coolingand work-up, the dark material so obtained, was chromatographed (silicagel; hexane/Et₂ O; 0-3%), giving: 2-nitro-5-phenoxytoluene, an orangeoil, 72.42 g (81%).

b) 5-Phenoxy-2-nitrotoluene (2.0 g, 8.72 mmol) and N-bromosuccinimide(2.33 g, 13.09 mmol) were stirred at 70° C. in DMF (30 mL) over a periodof 64 hr. Over this period additional NBS (total 1.87 g, 10.48 mmol) wasadded in four portions. The mixture was cooled and then partitionedbetween H₂ O/EtOAc. The organic extract was washed (H₂ O), dried (MgSO₄)and evaporated to give: 5-(4-bromophenoxy)-2-nitrotoluene as a yellowoil, (2.86 g) slightly contaminated with starting material, butsufficiently pure to be carried through to the next stage.

c) 5-(4-Bromophenoxy)-2-nitrotoluene (3.12 g), dimethylformamidediethylacetal (1.77 g, 2.1 mL, 12.02 mmol) and pyrrolidine (0.863 g, 1.01 mL,12.13 mmol) were heated in DMF (30 mL) at 120° C. for 2 hr. The DMF wasevaporated in vacuo to leave a deep red. oil. This was dissolved in MeOH(30 mL), and after cooling, Raney nickel (1 spatula) was added, followedby addition of hydrazine hydrate (1.8 mL; portionwise). After ca 1 hrthe Raney nickel was removed by filtration and the filtrate evaporated.The residue was worked-up (Et₂ O/sat.aq.NaCl) and chromatographed(silica gel; hexane/EtOAc; 0-10%) to afford, as a greenish solid:5-(4-bromophenoxy)indole, 0.394 g (ca 13%; containing tracecontaminants)

d) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(0.186 g, 0.25 mL, 1.83 mmol) in CH₂ Cl₂ (10 mL) with acetyl chloride(0.143 g, 0.13 mL, 1.83 mmol) followed by a solution of5-(4-bromophenoxy)indole (0.394 g, 1.37 mmol) in CH₂ Cl₂ (5 mL), gaveafter work-up 2-(N,N-dimethylaminomethyl)-5-(4-bromophenoxy)indole as abrown gum. This was treated with finely ground potassium cyanide (0.34g, 5.21 mmol) and methyl iodide (0.77 g, 0.34 mL, 5.44 mmol) in DMF (30mL) for 16 hr, and after appropriate work-up,3-cyanomethyl-5-(4-bromophenoxy)indole was obtained as a brown gum 0.29g, (ca 65%; carried through to next stage without further purification).

e) The cyanomethyl compound (0.29 g) was hydrogenated for 1 hr in MeOH(20 mL) and Me₂ NH (15 mL) over Raney nickel, at room temperature and 40psi. After work-up and treatment with BOC₂ O (excess) in ^(i) PrOH,evaporation gave a gum which was chromatographed (silica gel; CH₂ Cl₂/MeOH; 0-20%). The less polar component was not obtained pure and wasdiscarded. The more polar component:1-(N,N-dimethylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane wasobtained as a gum, 0.084 g (ca 25%). Further purification was effectedby prep. hplc, and the resulting material was treated with oxalic acid(0.012 g, 0.092 mmol) in MeOH/Et₂ O to give:1-(N,N-dimethylamino)-2-(5(4-bromophenoxy)indol-3-yl)ethane oxalate, anoff-white solid, 0.01 g (2%), m.p. 160°-62°.

EXAMPLE 14 1-(N,N-Dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane

This preparation was carried out in a similar manner to that describedabove for Example 11.

a) 5-Hydroxyindole (8.6 g, 64 mmol), 2-chloro-6-methoxypyrimidine (9.9g, 68 mmol) and powdered KOH (3.59 g, 64 mmol) were heated together inDMSO (70 mL) at 80° C. for 5 hr. After cooling and work-up,chromatography (hexane/EtOAc; 0-27%) gave:5-(4-methoxypyrimidin-2-yl)indole, 3.0 g, (18%).

b) Treatment of a cooled solution of N,N,N',N'-tetramethyldiaminomethane(1.18 g, 1.58 mL, 11.5 mmol) in CH₂ Cl₂ (10 mL) with acetyl chloride(0.90 g, 0.81 mL, 11.5 mmol) followed by a solution of5-(4-methoxypyrimidin-2-yloxy)indole (2.0 g, 8.2 mmol) in CH₂ Cl₂ (100mL), gave after work-up:3-(N,N-dimethylaminomethyl)-5-(4-methoxypyrimidin-2-yloxy)indole as awhite solid. This was treated with finely ground potassium cyanide (1.75g, 26.8 mmol) and methyl iodide (3.80 g, 1.65 mL, 26.8 mmol) in DMF (130mL) for 16 hr, and after appropriate work-up,3-cyanomethyl-5-(4-methoxypyrimidin-2-yloxy)indole was obtained as awhite solid, 2.20 g (96%).

c) The cyanomethyl compound (2.20 g, 7.8 mmol) was hydrogenated in MeOH(200 mL) and Me₂ NH (30 mL) for 2 hr over Raney nickel; at roomtemperature and 50 psi. After removal of the catalyst by filtration,evaporation gave a solid residue (1.8 g) which was treated with BOC₂ O(2.2 g, ca 10 mmol) in DMF (60 mL), at room temperature for 4 hr.Work-up (EtOAc/H₂ O) followed by chromatography (silica gel;hexane/EtOAc; 0-50% and then CH₂ Cl₂ /MeOH; 0-40%) gave two products:

(i)1-tert-butoxycarbonylamino-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane,a white solid, 0.23 g (8%) and

(ii)1-(N,N-dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane,a gum, 0.08 g (3%). The latter product was treated with oxalic acid inMeOH/Et₂ O to give:1-(N,N-dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethaneoxalate, a white solid, m.p. 203°-04° C. The less polar (^(t) BOC)product of the hydrogenation was unstable in the presence of acid.

EXAMPLE 153-(1-Methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole

a) 5-Bromo-1-triisopropylsilylindole (5.0 g, 14.19 mmol) was dissolvedin THF (dry; 60 mL) and, under an atmosphere of dry N₂, the solution wascooled to -65° C. tert-Butyllithium solution (1.7M in pentane; 30 mL,50.37 mmol) was added over ca 0.5 hr to give a yellow solution which wasstirred at -65° C. for a further 1 hr. A solution of2,2'-dipyridyldisulphide (15.72 g, 71.37 mmol) in THF (30 mL) was thenadded over a period of 20 min. and after a further 20 min at -65° C.,the mixture was allowed to warm slowly to room temperature and stirredfor ca 16 hr. Tetra-n-butylammonium fluoride solution (1.0M in THF; 30mL) was added, and after stirring at room temperature for 3 hr, saintedaqueous NaCl was added and the mixture extracted with Et₂ O. Theethereal layer was washed with saturated aqueous NaCl, dried (MgSO₄) andevaporated in vacuo. The residue was chromatographed (silica gel;hexane/Et₂ O; 0-40%) to afford: 5-(pyrid-2-ylthio)indole, as a creamcoloured solid, 1.98 g (62%).

The final stage of this preparation was carried out in a similar mannerto that of Example 8.

b) 5-(Pyrid-2-ylthio)indole (0.347 g, 1.53 mmol), 1-methylpiperid-4-one(0.347 g, 0.38 mL, 3.06 mmol), sodium methoxide (0.497 g) and somefinely ground molecular sieves were heated in refluxing MeOH (20 mL) for24 hr. After work-up and chromatography (silica gel; CH₂ Cl₂ /MeOH;0-15%),3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole wasobtained as a yellow solid (0.35 g). This was treated with fumaric acid(0.189 g, 1.6 mmol) in MeOH/Et₂ O to give, as a pale yellow crystallinesolid:3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indolefumarate, 0.227 g (34%), m.p. 226°-28° C.

EXAMPLE 16 1-(N,N-Dimethylamino)-2-(5-benzylindol-3-yl)ethane

a) 5-Bromo-1-triisopropylsilylindole (2.0 g, 5.68 mmol) was dissolved inTHF (dry, 30 mL) and the solution cooled to -70° C. tert-Butyllithium(1.7M in hexane; 10.7 mL, 18.2 mmol) was added, and by the time additionwas complete, a permanent yellow coloration had been produced. After afurther 1 hr at -65° C. benzaldehyde (0.658 g, 6.20 mmol) was added andthe mixture stirred at ca -65° C. for 1 hr before warming gradually toroom temperature H₂ O and NaCl were added to the mixture which was thenextracted (3×) with Et₂ O, and the extracts were combined, washed (H₂ O,3× and then saturated aqueous NaCl) and dried (MgSO₄). Evaporation gavea gum which was chromatographed (silica gel; hexane/Et₂ O; 0-30%).Recovered starting material, 0.437 g (22%) eluted first; followed by theproduct: phenyl(1-triisopropylsilylindol-5-yl)methanol, a gum whichsolidified on standing, 0.61 g (28%; several fractions containingcontaminated product were subsequently obtained). The pure product (0.6g, 1.58 mmol) was dissolved in THF (10 mL) and treated withtetra-n-butylammonium fluoride solution (1.0M in THF; 3.0 mL) at roomtemperature. The mixture was stirred for 1.5 hr and then partitionedbetween Et₂ O and saturated aqueous NaCl. After re-extracting theaqueous layer (Et₂ O; 2×), the combined ethereal layers were washed withsaturated aqueous NaCl, dried (MgSO₄) and evaporated to a gum which waschromatographed (silica gel; hexane/Et₂ O; 0-50%), giving:phenyl(indol-5-yl)methanol, as an almost colourless gum, 0.347 g (98%).This material was hydrogenated in EtOH (25 mL) over Pd-C (5%; a total of0.30 g was added over the reaction period, in two portions), at 45 psi,for ca 40 hr. The catalyst was filtered off, and the filtrate evaporatedto a gum which was chromatographed (silica gel; hexane/Et₂ O; 0-50%).The required product: 5-benzylindole, was obtained as an off whitesolid, 0.135 g (44%), as well as 5-benzylindoline 0.03 g, (10%) andunreacted starting material, 0.013 g (4%).

b) 5-Benzylindole (0.563 g, 2.716 mmol) was dissolved in dry Et₂ O (8mL) and the solution cooled in an ice-bath. A solution of oxalylchloride (0.47 g, 0.32 mL, 3.67 mmol) in dry Et₂ O (6 mL) was added overca 15 min. An orange precipitate was observed and after standing at ca4° C. for 16 hr, this solid was collected by filtration, and blown drywith a current of dry N₂. This acid chloride was immediately suspendedin dry CH₂ Cl₂ (35 mL), and while cooling (ice-bath) and stirring, asolution of Me₂ NH in Et₂ O was added (1.6M; 4.5 mL; freshly prepared)over 5 min. The starting material dissolved to give a very pale yellowsolution which was stirred at ice-bath temperature for 1 hr and thenallowed to warm to room temperature. This solution was then diluted withCH₂ Cl₂, washed successively with aq. K₂ CO₃, H₂ O and saturated aqueousNaCl, and dried (MgSO₄). Evaporation gave a solid which was trituratedwith Et₂ O to afford as a white powder:3-(N,N-dimethylglyoxamido)-5-benzylindole, 0.604 g (90%).

c) A solution of AlH₃ was prepared by addition of c.H₂ SO₄ (1.59 g)dropwise to a cooled (ice-bath) suspension of LiAlH₄ (1.226 g) in dryTHF (82 mL) over 20 min. The mixture was them left to stand under dry N₂for 1 hr to allow the solids to settle. A solution of the glyoxamide(0.59 g, 1.926 mmol) in THF (110 mL) was prepared, and in a N₂atmosphere, the AlH₃ solution (55 mL) was added over 5 min. The mixturewas stirred for 16 hr and then H₂ O was added dropwise to quench excessreagent, and the THF was evaporated in vacuo. The residue waspartitioned between 1M HCl/CH₂ Cl₁₂ and after re-extraction of theaqueous layer (2×; CH₂ Cl₂), the combined organic layers were washedwith 1M HCl and then saturated aqueous NaCl, dried (MgSO₄) andevaporated to a solid. Chromatography (silica gel; CH₂ Cl₂ /EtOHcontaining 2% concentrated aqueous NH₃ ; 0-12%), gave the free base:1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, as a gum, 0.246 g(46%). This was treated with oxalic acid (0.07 g) in MeOH (2 mL) and Et₂O added until crystallisation commenced. The product:1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane oxalate, was obtainedas white granular crystals, 0.191 g (27%), m.p.158°-9° C.

Pharmaceutical formulations

EXAMPLE A

A tablet for oral administration is prepared by combining

    ______________________________________                                                         Mg/Tablet                                                    ______________________________________                                        Compound of formula (I)                                                                          100                                                        lactose 153                                                                   starch 33                                                                     crospovidone       12                                                         microcrystalline cellulose                                                                       30                                                         magnesium stearate  2                                                                            330 mg                                                     ______________________________________                                    

into a 9 mm tablet.

EXAMPLE B

An injection for parenteral administration is prepared from thefollowing

    ______________________________________                                                         % w:w                                                        ______________________________________                                        Compound of formula (I)                                                                          0,50% (w:v)                                                1M citric acid     30% (v:v)                                                  sodium hydroxide (qs)                                                                            to pH 3.2                                                  water for injection BP                                                                           to 100 ml                                                  ______________________________________                                    

The compound of formula (I) is dissolved in the citric acid and the pHslowly adjusted to pH 3.2 with the sodium hydroxide solution. Thesolution is then made up to 100 ml with water, sterilised by filtrationand sealed into appropriately sized ampoules and vials.

We claim:
 1. A compound of structure (I): ##STR24## in which A¹ is O,S(O)_(n) in which n is 0,1 or 2, NR, CH₂, or CH(OH);A² is a bond or CH₂; or A¹ A² is CH═CH; R is hydrogen or C₁₋₄ alkyl; R¹ is a 6- to10-membered aryl or heteroaryl ring, optionally substituted by up to 3groups selected from halo, C₁₋₄ alkyl, hydroxy, oxo, C₁₋₄ alkoxy, --CO₂R⁹, --NHCOR⁹, --CONR¹⁰ R¹¹, --SO₂ NR¹⁰ R¹¹, --NHSO₂ R¹², NO₂, --NR¹⁰R¹¹, --NHCONH₂, CN, CF₃, or CF₃ O, wherein R⁹ to R¹¹ are independentlyhydrogen or C₁₋₄ alkyl and R¹² is C₁₋₄ alkyl; R² is hydrogen, halogen,C₁₋₄ alkyl, CN, NO₂ or CF₃ ; R³ is C(R⁴)(R⁵)CH₂ NR⁶ R⁷, --CH═NNHC(NH)NH₂or ##STR25## R⁴ and R⁵ are independently hydrogen or C₁₋₄ alkyl; R⁶ andR⁷ are the same or different and are each hydrogen or ₁₋₄ alkyl ortogether with the nitrogen atom to which they are attached form a ring;R⁸ is hydrogen, C₁₋₄ alkyl, or C₃₋₆ alkenyl; the dotted lines representan optional bond; and q and m are independently 1 or 2;andpharmaceutically acceptable salts, solvates and hydrates thereof, withthe proviso that R¹ is not a 6- to 10- membered aryl or heteroaryl ringoptionally substituted by up to 3 groups selected from halo, C₁₋₄ alkyl,CO₂ R⁹, NHCOR⁹, CONR¹⁰ R¹¹, SO₂ NR¹⁰ R¹¹, NHSO₂ R¹², NO₂, NR¹⁰ R¹¹,NHCONH₂ or CN, when A¹ A² is O, S or NH, R² is hydrogen and R³ is (CH₂)₂NR⁶ R⁷ or ##STR26## and with the further proviso that R¹ is not 3-CF₃-2-pyridyl, when A¹ A² is NH, R² is hydrogen and R³ is CH₂ CH₂ NMe₂. 2.A compound according to claim 1 where A¹ is O, S, NR or CH₂ and A² is abond or CH₂.
 3. A compound according to claim 1 where R¹ is optionallysubstituted phenyl or naphthyl.
 4. A compound according to claim 1wherein R¹ is an optionally substituted 6- to 10-membered heteroarylring containing from 1 to 4 nitrogen atoms.
 5. A compound according toclaim 1 wherein R² is hydrogen or halogen.
 6. A compound according toclaim 1 wherein R³ is --CH═NNHC(NH)NH₂ or C(R⁴)(R⁵)CH₂ NR⁶ R⁷ and R⁴ andR⁵ are both hydrogen or methyl.
 7. A compound according to any claim 1wherein R⁶ and R⁷ are both hydrogen or methyl.
 8. A compound accordingto claim 1 where R³ is a group ##STR27##
 9. A compound of structure (I)according to claim 1:3-(2-N,N-dimethylaminoethyl)-5-phenoxyindole,3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole,1-amino-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(4-methoxyphenoxy)indol-3-yl)ethane,1-amino-2-(5-(4-methylphenoxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(4-methylphenoxy)indol-3-yl)ethane,1-amino-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(3-trifluoromethylphenoxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(4-chloro-5-phenoxyindol-3-yl)ethane,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(4-methoxyphenoxy)indole,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl) -5-phenoxyindole,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-phenylthioindole,1-amino-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(pyrid-3-yloxy)indol-3-yl)ethane,1-amino-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(pyrimidin-2-yloxy)indol-3-yl)ethane,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-yloxy)indole,1-(N,N-dimethylamino)-2-(5-(4-bromophenoxy)indol-3-yl)ethane,1-(N,N-dimethylamino)-2-(5-(4-methoxypyrimidin-2-yloxy)indol-3-yl)ethane,3-(1-methyl-1,2,5,6-tetrahydropyrid-4-yl)-5-(pyrid-2-ylthio)indole,1-(N,N-dimethylamino)-2-(5-benzylindol-3-yl)ethane, or4-chloro-3-(2-N,N-dimethylaminoethyl)-5-phenylthioindole, or apharmaceutically acceptable salt, solvate or hydrate thereof.
 10. Apharmaceutical composition comprising a compound of structure (I) asdefined in claim 1 or a pharmaceutically acceptable salt, solvate orhydrate thereof and a pharmaceutically acceptable carrier.
 11. A methodof treatment of a condition which requires modulation of the 5-HT₁ -likereceptor which comprises administering to a subject in need thereof aneffective amount of a compound of structure (I) as defined in claim 1 ora pharmaceutically acceptable salt, solvate or hydrate thereof.